We defined a novel regulatory pathway in the respiratory tract. In a murine model, we showed that Th1- and Th2-induced airway inflammation followed by repeated exposure to inhaled antigen leads to a state of immunosuppression. Challenge of these animals with a marked population of TCR Tg effector Th1 or Th2 cells results in striking inhibition of inflammation and effector Th cells. In Th2 models, AHR, mucus and eosinophilia are reduced. We call this pathway Airway Inflammation-Related Inhibition of Disease (AIRID). AIRID is antigen non-specific, can be induced in lymphocyte deficient mice and is associated with a population of TGF-21- expressing macrophages. Our latest studies show that AIRID is macrophage-mediated and requires TLR signals for its induction. We hypothesize that AIRID is a regulatory pathway in the lung that is induced by repeated exposure to inhaled pathogen-associated molecular patterns (PAMPs), resulting in differentiation of a population of immunosuppressive macrophages. AIRID results in potent inhibition of effector Th1 and Th2 responses through the production of macrophage- and epithelial-derived mediators. AIRID is a powerful method to inhibit effector T cell responses. This pathway may exist to block immune responses when there is repeated inhalational exposure to non-pathogenic substances and to resolve ongoing inflammatory responses. Induction of this pathway may offer potent, localized treatment of chronic T cell-mediated respiratory illnesses, such as asthma and sarcoidosis, and provide insights into the development of such diseases. In this proposal we will: Aim I. Define how innate immune signals stimulate AIRID. Aim II. Define mechanisms of immunosuppression in AIRID. Aim III. Determine if AIRID can be induced to treat inflammatory lung diseases. Project Narrative: This proposal investigates a novel protective pathway in the respiratory tract that controls lung inflammation. We will define the cells and factors that are responsible for the protective effect and determine if this pathway can be activated to treat chronic lung diseases, such as asthma and sarcoidosis.